Abstract

Many components contribute to immunodominance in the response to a complex virus, but their relative importance is unclear. This was addressed using vaccinia virus and HLA-A*0201 as the model system. A comprehensive analysis of 18 viral proteins recognized by CD8+ T cell responses demonstrated that about 1/40 of all possible 9–10 mer peptides were high-affinity A*0201 binders. Peptide immunization and T cell recognition data generated from 91 peptides indicated that about half of the binders were capable of eliciting T cell responses, and that 1/7 immunogenic peptides are generated by natural processing. Based on these results, we estimate that vaccinia virus encodes about 150 dominant and subdominant epitopes restricted in the context of HLA-A*0201. However, of all these potential epitopes, only 15 are immunodominant and actually recognized in vivo during vaccinia virus infection of HLA-A*0201 transgenic mice. Neither peptide binding affinity, complex stability, TCR avidity nor amount of processed epitope appeared to strictly correlate with immunodominance status. Further experiments suggested that vaccinia infection impairs the development of responses directed against subdominant epitopes. This suggested that immunoregulatory factors restrict the repertoire of T cell specificities following vaccinia infection by at least a factor of ten.